title: Partial neural protection with prophylactic low-dose melatonin after asphyxia in preterm fetal sheep.
abstract: Melatonin is a naturally occurring indolamine with mild antioxidant properties that is neuroprotective in perinatal animals. There is limited information on its effects on preterm brain injury. In this study, 23 chronically instrumented fetal sheep received 25 minutes of complete umbilical cord occlusion at 101 to 104 days gestation (term is 147 days). Melatonin was administered to the ewe 15 minutes before occlusion (0.1 mg/kg bolus followed by 0.1 mg/kg per hour for 6 hours, n=8), or the equivalent volume of vehicle (2% ethanol, n=7), or saline (n=8), or maternal saline plus sham occlusion (n=8). Sheep were killed after 7 days recovery in utero. Fetal blood pressure, heart rate, nuchal activity, and temperature were similar between groups. Vehicle infusion was associated with improved neuronal survival in the caudate nucleus, but greater neuronal loss in the regions of the hippocampus, with reduced proliferation and increased ameboid microglia in the white matter (P<0.05). Maternal melatonin infusion was associated with faster recovery of fetal EEG, prolonged reduction in carotid blood flow, similar neuronal survival to vehicle, improved numbers of mature oligodendrocytes, and reduced microglial activation in the white matter (P<0.05). Prophylactic maternal melatonin treatment is partially protective but its effects may be partly confounded by ethanol used to dissolve melatonin.
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Drury
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Joanne O
authors.initials: JO
authors.lastname: Davidson
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Laura
authors.initials: L
authors.lastname: Bennet
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Lindsea C
authors.initials: LC
authors.lastname: Booth
authors.affiliation: Department of Pediatrics, NorthShore University HealthSystem, Evanston, Illinois, USA.
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Mhoyra
authors.initials: M
authors.lastname: Fraser
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Lotte G
authors.initials: LG
authors.lastname: van den Heuij
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Gunn
mesh_terms: D000818:Animals; D001238:Asphyxia Neonatorum / Q000517:prevention & control*; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000009:adverse effects / Q000737:chemistry; D000431:Ethanol / Q000009:adverse effects / Q000737:chemistry; D005260:Female; D005311:Fetal Hypoxia / Q000473:pathology*; D005865:Gestational Age; D008431:Maternal-Fetal Exchange; D008550:Melatonin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011247:Pregnancy; D011292:Premedication; D012756:Sheep / Q000196:embryology
chemical_list: D004337:Drug Carriers; D018696:Neuroprotective Agents; D000431:Ethanol; D008550:Melatonin